1285

Mattresses and cot death SiR,—Your note (April 20, p 969) on my work on the generation of phosphine, arsine, stibine, and related alkyl compounds through mattress biodeterioration and their possible role in cot death,’ casts doubt on the involvement of these toxic gases because the symptoms normally associated with poisoning, particularly erythrocyte haemolysis, are not seen in cot death. You suggest that hypoxia is more likely to be involved. Unfortunately, you failed to explain that the normal symptoms of poisoning are those that are observable, and that there is a less obvious poisoning action that is entirely consistent with all reported features of cot death, including hypoxia. These gases have a powerful anticholinesterase action, and this explains reports of depression of the central nervous system in standard toxicological references. Infants breathing high concentrations of these gases will suffer destruction of blood cholinesterase and progressive accumulation of acetylcholine

generated by the vagus nerve, resulting in cardiac failure before any other symptoms can develop. High concentrations of these gases occur when infants are overwrapped because the higher temperatures accelerate the biodeterioration of the mattresses; infants in the prone position are most at risk because these gases are heavier than air. Overwrapping and prone position are usually associated with cot death. 3-5 Your account of our work suggests that phosphine, arsine, and stibine are generated only by deterioration of polyvinyl chloride cot mattress coverings, and that phosphine and stibine are derived from fire retardants based on phosphorus and antimony compounds. However, fire retardants in other coverings and foam fillings are also implicated.2 Lambskin mattresses can also generate arsine or stibine. Arsenic poisoning results in arsenic deposits in hair, and if grass contaminated by soil containing arsenic or these elements are deposited in the wool; Z Wool biodeterioration then generates the toxic gases.2 contamination may be the explanation for the pockets of very high cot death rates in parts of Australia and New Zealand where lambskins are normally used as cot mattresses.

sheep

feed

on

antimony,

Penarth Research International Ltd, P0 Box 142, St Peter Port, Guernsey, Channel Islands

B. A. RICHARDSON

1. Richardson BA. Cot mattress biodeterioration and SIDS. Lancet 1990; 335: 670. 2 Richardson BA. Mattress biodeterioration and toxic gas generation: a possible cause of sudden infant death. Clin Ecol (in press). 3 Engelberts AC, de Jonge GA. Choice of sleeping positions for infants. Arch Dis Child

1990; 65: 462-67. EAS, Taylor BJ, Weatherall IL. Sleeping position and infant death bedding may predispose to hyperthermia and sudden infant death syndrome. Lancet 1989; i:

4 Nelson

involved in domestic fire and the ratio of deaths before and after inception of the 1988 regulations support this possibility. There has been a rising trend since 1985 when manufacturers started to anticipate the regulations. There seems to be a lack of advice to mothers on cot bedding hygiene. Mattresses having open weave net or other covering over an exposed foam interior should be avoided because they are impossible to clean unless the cover is removable and the exposed foam is frequently washed and dried. Those covered with plastic should be wiped every day with clean water and detergent and periodically the wash water should contain a bacteriostat. The whole mattress, after cleaning, should be exposed as often as possible to sunlight outdoors. A new baby needs a new mattress, and for small-for-age or other at-risk infants a new mattress should be purchased between the sixth and tenth month after birth. In all but 2 of 140 cases of SIDS investigated by B. A. Richardson (personal communication) the mattress had been used for an older sibling or otherwise reused. Richardson’s theory may be refuted by further investigation but your note’s reference to accounts of acute poisoning by one or other of the gases and the comment that SIDS victims lack the pathological signs noted in such acute episodes does not constitute investigation. If Richardson’s findings are revelant to SIDS, the poisoning is periodic, chronic, and variable and at levels well below those associated with acute poisoning. A Department of Health working group has been expected to report on the matter since mid-1990. Interestingly, the rate of infant death where SIDS is implicated seems to have been less for 1989 than for any of the previous seven years. Perhaps the publicity which followed the initial report by Richardson in June, 1989, also had some pre-emptive effect. Toxic effects of low-level gas concentrations are not easy to investigate. Since the anticholinesterase action of phosphine may be involved those studying victims of military use of toxic gases may be best equipped to investigate cot deaths. Richardson is merely saying that infants may be required to sleep in an environment that is contaminated avoidably. The statement that hypoxia very probably contributes to SIDS begs the question-why should hypoxia develop suddenly in an apparently normal infant? Hyperthermia may be responsible in part, but a rise in environmental temperature would also increase emission of toxic gases. There is a precedent. The emission of arsine from wallpaper and domestic fabrics was well-understood1 for almost half a century before the last reported2 death from this cause in the UK. "Langlaw", Whitehill, Dalkeith EH22 2QG, UK

199-201. 5

Azaz Y, et al. Interaction between bedding and sleeping position in sudden infant death syndrome; a population based case-control study.

Fleming PJ, Gilbert R, Br Med

J1990; 301: 85-89.

damns by faint praise facts which, of sudden infant death syndrome profound consideration. Scopulariopsis bervicaulis is a frequent contaminant of the domestic environment and of cot mattresses in particular. Growth of this organism may be encouraged by substrates containing arsenical biocides or fire retardants such as antimony trioxide and phosphate plasticisers from which it can generate arsine, stibine, and phosphine. Domestic furnishings, including cot mattresses, often contain these substances, as approved by the Furniture and Furnishings (Fire) (Safety) Regulations 1988. Thus, whatever may be the cause(s) of SIDS, infants are required to sleep in an environment that can contain worrying levels of highly toxic gases. Is this sensible? Biocides at low concentration may encourage bacterial or fungal growth. Fire retardants do not prevent burning of otherwise flammable materials; they merely discourage the initiation of fire. A house fire is not likely to start by ignition of a cot mattress, and any infant caught in such a conflagration will probably have died by inhalation of smoke or other toxic materials before the mattress catches fire. Why, therefore, treat cot bedding with fire retardants? It may even be that an infant involved in a domestic fire is at greater risk of asphyxiation if lying on a treated mattress. Home Office figures (given in Hansard on March 19, 1991) on cot-age infants

SiR,—Your April 20

whilst

JOHN G. WATT

On chronic arsenical poisoning from wallpapers and fabrics. Proc Am Acad Arts Sci 1894; 21: 148-77. 2 Anon. Gaseous arsenic from wall-plaster. Analyst 1932, 57: 163-64. 1.

Sanger CR.

note

not proven associates (SIDS), do warrant more

Inhibition of natural anti-inflammatory mechanism by &bgr;2-agonists SIR,-Dr Johnson and colleagues (April 20, p 982) argue that my hypothesis (March 23, p 717) is flawed; they claim that I "ignore the probable consequences of the relevance of proinflammatory mediators from

cells and focus instead on evidence for the properties of heparin". My critics have not

mast

anti-inflammatory understood my hypothesis. My thinking in this area was prompted by the failure of specific mast-cell-stabilising drugs, developed as a consequence of a large programme of research, to show clinical efficacy in asthma. These drugs inhibited allergen-induced bronchospasm, thought to be due to mast-cell-derived spasmogens, but not other aspects of allergic asthma, leading to the conclusion that the plethora of potentially pro-inflammatory mast-cell-derived mediators are not important in man for anything other than inducing acute bronchoconstriction. I dismissed pro-inflammatory mediators derived from mast cells as being important in the pathogenesis of asthma because glucocorticosteroids, despite their potent anti-inflammatory action, have no effect at therapeutic concentrations on the release of mediators from mast cells.

1286

Johnson et al claim that heparin has proinflammatory actions, but where is their evidence? I cited thirteen publications, based substantially on in-vivo experiments, showing that heparin-like molecules are anti-inflammatory. They also state that "the antiinflammatory profile of salmeterol mimicks that claimed by Page for heparin". Unless Johnson et al have in-vivo evidence that salmeterol inhibits lymphocyte trafficking, delayed hypersensitivity responses, and smooth muscle and fibroblast proliferation, its anti-inflammatory profile is, I suggest, trivial beside that of heparin. Others have failed to reproduce their claim that salmeterol inhibits eosinophil infiltration except at concentrations well in excess of those required to inhibit airway smooth muscle constriction.’1 Furthermore, this property is not unique to salmeterol among the (32 agonists 2 Moreover, two recent reports suggest that &bgr;2-agonists can up-regulate IgE receptors on human monocytes3 and potentiate the ability of interleukin-4 to induce IgE synthesis by human

B-lymphocytes.4 There is good evidence that &bgr;2-agonists exacerbate bronchial hyperresponsiveness,5-7 and current research suggests that bronchial hyperresponsiveness can be exacerbated by airways inflammation. Until regular use of &bgr;2-agonists has been formally exacerbate airways inflammation and the subepithelial scar tissue, the caution resulting deposition expressed in my hypothesis remains reasonable. I remain convinced that "scientists and clinicians should err on the side of caution when evaluating the claim that salmeterol is anti-imflammatory by virtue of its ability to inhibit mast cell degranulation". If the manufacturers are so convinced that salmeterol is antiinflammatory why is this drug, launched as "A new type of &bgr;2-agonist which provides a long lasting bronchodilatation and has anti-inflammatory activity", now being advertised with the antiinflammatory claim relegated to the small print? shown

not to

induce

or

of

of disease but also age at onset and duration of illness in naturally occurring familial cases.7 The common PrP gene polymorphism at codon 129 (allele frequency 0-68 methionine, 0-32 valine in whitest is a candidate. We have analysed age at death of affected individuals in a large pedigree with inherited prion disease linked to a 144 base-pair insertion within the PrP open reading frame.9 (It was not possible to ascertain age at onset for patients who had died long ago.) In 35 cases death was thought to have been a direct consequence of the illness (excluding accidental death and suicide). When maximum likelihood estimate procedures were applied to ages at death, two normal distributions with equal standard deviations gave a significantly better fit than one normal distribution (xzz = 13- 1; p < 0-01). Calculations suggested that 26% of cases fell into a "late" age at death group (mean 56-9 years [SD 3-5]), the remaining 74% comprising an "early" age at death group (42-7 [3’5] years). We designated the deaths below age 51 as "early" (26 cases) and the remainder as "late". The 144 bp insertion in the gene in this family is within a Metlz9 encoding allele."’ We have now determined the polymorphism in the normal allele in 13 affected members of this pedigree-4 "late" (2 died and 2 alive over age 50); 6 "early" (3 died under age 50 and 3 whose age at onset, illness severity, and present age [below 35] justify this classification). All 4 in the late group carried the Val"’ allele and all 6 in the early group carried the Metlz9 allele (Fisher’s exact test, p 0-0048). Three affected individuals (unclassified but below age 50) also carried the Met129 allele. Thus aminoacid polymorphisms within the normal allele do seem to influence age at death in familial prion disease. The critical factor for later death may be allelic heterozygosity between normal and mutant alleles. =

Biomedical Sciences Division,

King’s College London, London SW3 6LX, UK

C. P. PAGE

K, Marguin V, Bouhelal R, Morley J. Failure of long acting betaadrenoceptor agonists to diminish allergic eosinophilia of the airways m guinea pigs. Br J Pharmacol (in press). Fugner A. Formation of oedema and accumulation of eosinophils in the guinea pig lung: inhibition by inhaled beta-stimulants Int Arch Allergy Appl Imunol 1989; 88:

1. Boubekeur

2.

225-27.

3. Dugas B, Coqueret O, Paul-Eugene N, Mencia-Huerta JM, Braquet P. &bgr;-adrenoceptor agonists promote IL-4 induced human B-lymphocyte activation, proliferation and differention. FASEB J 1991; 5 (part II): A1011. 4. Dugas B, Lagente V, Paul-Eugene N, et al. 4th Interscience World Conference on inflammation, anti-rheumatics, analgesics and immunomodulators (Geneva, April 15-18, 1991); abstr 409. 5. Kerrebijn KF, van Essen-Zandvilet EEM, Neijens HJ. Effects of long term treatment with inhaled corticosteroids and beta agonists on bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987; 76: 628-36. 6. Vathenen AS, Knox AJ, Higgins BG, et al. Rebound increase in bronchial hyperresponsiveness after treatment with inhaled terbutaline. Lancet 1988; i: 554-58. 7. Van Schayck CP, Visch MB, von Herwaarden CLA, Dorpeling E, Van Wed C. Increased bronchial hyperresponsiveness after inhaling salbutamol during one year is not caused by desensitisation to salmeterol. J Allergy Clin Immunol 1990; 86: 793-800.

Aminoacid polymorphism in human prion protein and age at death in inherited prion disease

Division of Psychiatry, Clinical Research Centre, Harrow HA1 3UJ, UK

H. F. BAKER M. POULTER T. J. CROW C. D. FRITH R. LOFTHOUSE R. M. RIDLEY

Department of Biochemistry and Molecular Medicine, St Mary’s Hospital Medical School, London W2

J. COLLINGE

1. Masters CL, Gajdusek DC, Gibbs CJ. The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer’s disease. Brain 1981, 104: 535-58. 2. Masters CL, Gajdusek DC, Gibbs CJ. Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Straussler syndrome. Brain 1981; 104: 559-88 3. Westaway D, Goodman PA, Mirenda CA, et al. Distinct pnon proteins m short and long scrapie incubation period mice. Cell 1987; 51: 651-62. 4. Hsiao K, Baker HF, Crow TJ, et al. Linkage of a pnon protein missense variant to the Gerstmann-Sträussler syndrome. Nature 1989; 338: 342-45. 5. Hsiao K, Scott M, Foster D, et al Spontaneous neurologic disease in transgenic mice expressing leucine mutant pnon protein of Gerstmann-Straussler syndrome Science 1990; 250: 1587-90. 6. Prusiner SB, Scott M, Foster D, et al. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie pnon replication. Cell 1990; 63: 673-86. 7. Ridley RM, Baker HF, Crow TJ. Experimental transmission and autosomal dominant inheritance of the Gerstmann-Straussler syndrome In: Unconventional virus diseases of the central nervous system (Court LA, Dormont D, Brown P, Kingsbury DT, eds. Fontenay-aux-Roses. Commissariat à l’Energie Atomique, 1989: 123-41. 8. Owen F, Poulter M, Collinge J, Crow TJ. Codon 129 changes in the pnon protein gene in Caucasians. Am J Hum Genet 1990; 46: 1215-16. 9. Collinge J, Harding AE, Owen F, et al. Diagnosis of Gerstmann-Straussler syndrome in familial dementia with prion protein gene analysis. Lancet 1989, ii: 15-17 10. Owen F, Poulter M, Collinge J, et al. Insertions in the pnon protein gene m atypical dementias. Exp Neurol (in press).

SiR,—The inherited prion diseases cause death in middle age: age at death for Creutzfeldt-Jakob disease is 51 years and for Gerstmann-Straussler syndrome it is 48, although the range is wide, from 20 to 73. Polymorphisms within the murine prion protein (PrP) gene control incubation periods in experimental transmission of scrapie to mice,3 and mutations within the PrP gene have been linked to prion diseases in man.4 Homologues of these human mutations are sufficient to cause disease in transgenic mice. In mice the ease of experimental transmission and the incubation period are controlled by the sequence homology between the disease-related

SiR,—Two cases of confusion between the drugs ’Losec’ (omeprazole) and ’Lasix’ (frusemide), because of similarities in the spelling of their brand names, have been reported.’ The errors were recognised after only a few doses had been given, without ill-effects.

form of the PrP used to transmit disease and the normal cellular PrP of the host.6 Thus sequence homology between the normal and the disease-related allele may be relevant to the disease process in inherited prion diseases. We have argued that polymorphisms within the PrP gene may influence - not only the occurrence

A 59-year-old woman was admitted to our hospital with a diagnosis of pyelonephritis. She had diabetes, hypertension, a history of myocardial infarction, and a recently diagnosed duodenal ulcer. On admission she was taking antibiotics, insulin, clonidine, nifedipine, antacids, and omeprazole. On day 3 she had abundant

mean

Fatal confusion between ’Losec’ and ’Lasix’